Investigations into the parallel kinetic resolution of acetyl mandelic acid

Article abstract of DOI:10.1016/j.tetlet.2008.10.062

The resolution of a series of active esters (derived from acetyl mandelic acid) using an equimolar combination of quasi-enantiomeric oxazolidin-2-ones is discussed. The levels of diastereoselectivity and the facial selectivity were found to be dependent on the structural nature of the pro-leaving group.

Full text of DOI:10.1016/j.tetlet.2008.10.062

Tetrahedron Letters 49 (2008) 7398–7402
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Tetrahedron Letters
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Investigations into the parallel kinetic resolution of acetyl mandelic acid
*
Sameer Chavda, Elliot Coulbeck, Jason Eames
Department of Chemistry, University of Hull, Cottingham Road, Kingston Upon Hull HU6 7RX, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The resolution of a series of active esters (derived from acetyl mandelic acid) using an equimolar combi-
nation of quasi-enantiomeric oxazolidin-2-ones is discussed. The levels of diastereoselectivity and the
facial selectivity were found to be dependent on the structural nature of the pro-leaving group.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 4 September 2008
Revised 3 October 2008
Accepted 14 October 2008
Available online 18 October 2008
The resolution and synthesis of pharmaceutically important1
enantiomerically pure 2-phenylpropionic acid and its derivatives
are well documented.2–4 Over the last few years, we have been
interested in the parallel kinetic resolution5–7 of pentafluorophenyl
2-phenylpropionate (rac)-3 (and its structurally related deriva-
tives)8 using an equimolar combination of quasi-enantiomeric9
oxazolidin-2-ones (R)-1 and (S)-2 as resolving agents. Addition of
pentafluorophenyl 2-phenylpropionate (rac)-3 to a stirred solution
of lithiated Evans oxazolidin-2-ones (formed by treating an equi-
molar combination of (R)-1 and (S)-2 with n-BuLi in THF at
ꢀ78 °C) gave after 2 h, a separable diastereoisomeric mixture of
oxazolidin-2-one adducts (S,R)-syn-4 (in 60% yield with 90% de)
and (R,S)-syn-5 (in 60% yield with 78% de) (Scheme 1).
Ph
CO2C6F5
Ph
CO2H
Ph
CO2H
Ph
CO2C6F5
H
OMe
H
OAc
H
OH
H
OAc
(rac)-6
(rac)-8
(rac)-7
(rac)-9
Scheme 2. Active esters (rac)-6 and (rac)-9.
tate (rac)-6 (Scheme 2) using this combination of oxazolidin-2-
ones (R)-1 and (S)-2 with some success leading to the correspond-
ing oxazolidin-2-one adducts with up to 78% de. In an attempt to
better understand these parallel kinetic resolutions, we were inter-
ested in the resolution of 2-hydroxycarboxylic acids, such as man-
delic acid (2-hydroxy-2-phenyl-acetic acid) (rac)-7 (Scheme 2). We
chose to protect the C(2) hydroxyl substituent of mandelic acid
(rac)-7 as an acetate [acetyl mandelic acid (rac)-8] to limit its
nucleophilic and acidic character (Scheme 2).11
We recently extended10 this methodology towards the parallel
kinetic resolution of pentafluorophenyl 2-methoxy-2-phenyl-ace-
We now report an extension to this methodology for the reso-
lution of pentafluorophenyl 2-acetoxy-2-phenyl acetate (rac)-9
using a quasi-enantiomeric combination of Evans’ oxazolidin-2-
ones (Scheme 2). We first investigated the level of mutual recogni-
tion between pentafluorophenyl 2-acetoxy-2-phenyl acetate (rac)-
9 [formed in 86% yield by addition of pentafluorophenol to a solu-
tion of DCC and 2-acetoxy 2-phenylacetic acid (rac)-8] and the
(lithiated) oxazolidin-2-one (rac)-1 (Scheme 3). Treatment of
(rac)-1 with n-BuLi in THF at ꢀ78 °C, followed by the addition of
O
O
1. n-BuLi
THF, -78 ºC
HN
O
HN
O
Ph
CO2C6F5
2.
Ph
i-Pr
H
Me
(R)-1
(S)-2
(rac)-3
O
O
O
O
Ph
Ph
N
O
N
O
1. n-BuLi
THF, -78 ºC
O
O
O
Me
H
H
Me
Ph
Ph
i-Pr
HN
O
N
O
2.
F
OAc
(S,R)-syn-4: (R,R)-anti-4
(R,S)-syn-5: (S,S)-anti-5
OAc
F
O
95:5 (60%)
88:12 (60%)
Ph
Ph
(rac)-1
Ph
O
Scheme 1. Parallel kinetic resolution of active ester (rac)-3 using quasi-enantio-
meric oxazolidin-2-ones (R)-1 and (S)-2.
(rac)-syn-10:(rac)-anti-10
F
F
50:50 (48%)
F
(rac)-9
* Corresponding author. Tel.: +44 1482 466401; fax: +44 1482 466410.
E-mail address: j.eames@hull.ac.uk (J. Eames).
Scheme 3. Mutual kinetic resolution of active ester (rac)-9 using oxazolidin-2-one
(rac)-1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.062

S. Chavda et al. / Tetrahedron Letters 49 (2008) 7398–7402
7399
active ester (rac)-9, gave after 2 h, the corresponding oxazolidin-2-
one adducts (rac)-anti- and (rac)-syn-10 in 48% yield with no levels
of mutual selection (Scheme 3). Intrigued by this apparent loss of
stereoselection (78% de10?0% de) by the subtle substituent change
from MeO- [in (rac)-6] to a AcO- [in (rac)-9], we next chose to
investigate the structural nature of the pro-leaving group in an at-
tempt to improve the levels of diastereoselection.
phenolate pro-leaving group substantially lowered the levels of
mutual recognition between the associated active ester and the
parent oxazolidin-2-one (rac)-1. From this limited study, it appears
that 4-chlorophenyl 2-acetoxy-2-phenylacetate (rac)-13 was the
optimum active ester for high levels of mutual recognition
(Scheme 4, entry 3).
With this information in hand, we next focussed our attention
on finding a complementary quasi-enantiomeric oxazolidin-2-one
partner for 1 to enable efficient parallel kinetic resolution of 4-
chlorophenyl 2-acetoxy-2-phenylacetate (rac)-13 (Scheme 5). We
chose to screen four structurally related oxazolidin-2-ones (rac)-
2, (rac)-20–21 and (rac)-syn-22 under our standard mutual kinetic
resolution conditions. Deprotonation of oxazolidin-2-ones (rac)-2,
(rac)-20–21 and (rac)-syn-22 in THF at ꢀ78 °C with n-BuLi,
followed by the addition of active ester (rac)-13, gave after 2 h,
separable diastereoisomeric mixtures of oxazolidin-2-ones (rac)-
syn- and (rac)-anti-23 (in 23% yield with a ratio of 33:67), (rac)-
syn- and (rac)-anti-24 (in 56% yield with a ratio of 43:57), (rac)-
syn- and (rac)-anti-25 (in 44% yield with a ratio of 84:16) and
(rac)-syn,syn- and (rac)-anti,syn-26 (in 52% yield with a ratio of
70:30), respectively (Scheme 5).
These molecular recognition processes were found to be depen-
dent on the structural nature and size of the C(4)-substituent with-
in the oxazolidin-2-ones (rac)-2, (rac)-20–21 and (rac)-syn-22. The
diastereoselectivity changed from favouring syn- to anti-adduct
formation for oxazolidin-2-ones, which contained a sterically
demanding C(4)-sp3-hybridised substituent; from 40% de favour-
ing syn-26 [for (rac)-syn-22], 14% de favouring anti-24 [CH2Ph in
(rac)-20], through to 34% de favouring anti-23 [CHMe2 in (rac)-2]
(Scheme 5). By comparison, oxazolidin-2-ones, such as (rac)-1
and (rac)-21, which contained a C(4)-sp2-hybridised substituent fa-
We first chose to screen the simplest active ester, phenyl 2-
acetoxy-2-phenylacetate (rac)-11, with the (lithiated) oxazolidin-
2-one (rac)-1 under our standard mutual kinetic resolution condi-
tions in order to get a measure of the natural diastereoselection
(Scheme 4, entry 1). Deprotonation of the oxazolidin-2-one (rac)-
1 with n-BuLi in THF at ꢀ78 °C, followed by the addition of active
ester (rac)-11, gave after 2 h, the corresponding oxazolidin-2-one
adducts (rac)-syn- and (rac)-anti-10 in 24% yield with good levels
of mutual selection (ratio 87:13) (Scheme 4, entry 1). The syn-dia-
stereoisomer (rac)-syn-10 was found to be the major product. In an
attempt to improve the overall yield of this resolution, we next
screened a series of 4-halo-substituted active esters (rac)-12–14
(X = F, Cl and Br), which contained an electron-withdrawing group
to increase their electrophilicity and to aid their pro-leaving ability
(Scheme 4, entries 2–4). Treatment of the oxazolidin-2-one (rac)-1
with n-BuLi in THF at ꢀ78 °C, followed by the addition of active es-
ters (rac)-12–14, gave after 2 h, the corresponding oxazolidin-2-
one adducts (rac)-syn-10 in higher yield (ꢁ40%) with comparable
levels of diastereoselection (76% de) (Scheme 4, entries 2–4).
Whereas for a less electrophilic active ester, which contained an
electron-donating 4-methoxyphenyl-substituent, such as (rac)-15,
the reaction did not proceed under our standard reaction condi-
tions (THF, ꢀ78 °C, 2 h) (Scheme 4, entry 5).
Our attention next turned to studying the mutual kinetic reso-
lution of a related series of 2-substituted-phenyl active esters
(rac)-16–19 (X = F, Cl, Br and OMe) using the oxazolidin-2-one
(rac)-1 in an effort to better understand the steric and potential
co-ordination effects (Scheme 4, entries 6–9). Addition of these
active esters (rac)-16–19 to a stirred solution of (lithiated) oxazoli-
din-2-one (rac)-1 in THF at ꢀ78 °C, gave after 2 h, the correspond-
ing oxazolidin-2-one adducts (rac)-syn- and (rac)-anti-10 in 0–58%
yields with little or no diastereoselection (0–14% de) (Scheme 4,
entries 6–9). From this study, it was evident that a 2-substituted-
1.
2.
n-BuLi
THF, -78 ºC
O
O
O
Ph
HN
O
N
O
OAc
O
OAc
Ph
i
-Pr
i
-Pr
O
Cl
(
rac)-2
(
rac
)
-syn-23:(rac)-anti-23
33:67 (23%)
(
rac)-13
1. n-BuLi
THF, -78 ºC
O
O
O
O
O
1. n-BuLi
THF, -78 ºC
O
Ph
N
O
HN
O
2.
Ph
OAc
O
Ph
HN
O
N
O
OAc
2.
OAc
X
Bn
O
Bn
OAc
O
Ph
Cl
Ph
Ph
O
(
rac)-20
(
rac
)
-syn-24:(rac)-anti-24
43:57 (56%)
(
rac)-13
(rac)-1
(rac)-syn-10: (rac)-anti-10
11-19
1. n-BuLi
THF, -78 ºC
O
O
O
Entry
syn-10:anti-10
Yield
Active esters
Ph
HN
O
N
O
2.
87:13
87:13
24%
45%
(rac)-11; X = H
(rac)-12; X = F
1
2
3
4
5
OAc
O
OAc
OAc
EtO2C
Ph
EtO2C
O
Ph
O
88:12
87:13
40%
42%
0%
(rac)-13; X = Cl
(rac)-14; X =Br
(rac)-15; X = OMe
Cl
(
rac
)
-syn-25:(rac)-anti-25
84:16 (44%)
(
rac)-21
O
(
rac)-13
X
O
O
O
1.
2.
n-BuLi
THF, -78 ºC
Ph
(rac)-16; X = F
(rac)-17; X = Cl
(rac)-18; X = Br
6
7
57:43
50:50
47:53
40%
58%
36%
HN
O
N
O
X
OAc
OAc
O
OAc
O
Ph
Ph
8
9
Me
Ph
Me
Ph
O
O
Cl
(rac)-19; X = OMe
0%
(
rac
)
-syn
,
syn-26:(rac)-anti,syn-26
70:30 (52%)
(
rac)-syn-22
(
rac)-13
Scheme 4. Mutual kinetic resolution of active esters (rac)-11–19 using oxazolidin-
2-one (rac)-1.
Scheme 5. Mutual kinetic resolution of active ester (rac)-13 using oxazolidin-2-
ones (rac)-2, (rac)-20–21 and (rac)-syn-21.

7400
S. Chavda et al. / Tetrahedron Letters 49 (2008) 7398–7402
voured syn-adducts 10 and 25 with 74% de and 68% de, respec-
tively (Schemes 4 and 5).
F
F
Cl
MeO
F
F
F
O
O
With the completion of this preliminary study, we now turned
our attention towards the parallel kinetic resolution of pentafluor-
ophenyl 2-acetoxy-2-phenyl acetate (rac)-13 using a combination
of quasi-enantiomeric oxazolidin-2-ones. For our study, we chose
to investigate the use of two combinations of oxazolidin-2-ones,
Ph
O
O
H
OAc
Me
H
(S)-27
(R)-13
namely
a mismatched combination [(R)-1 and (S)-2] and a
Scheme 8. Quasi-enantiomeric active esters (R)-13 and (S)-27.
matched combination [(S)-1 and (S)-21], to better understand their
relative dominance (Schemes 6 and 7).
For the mismatched combination of oxazolidin-2-ones (R)-1
and (S)-2, treatment with n-BuLi in THF at ꢀ78 °C, followed by
the addition of active ester (rac)-13, gave a separable combination
of oxazolidin-2-ones (S,R)-syn- and (R,R)-anti-10 [in 48% yield in a
83:17 ratio derived from (R)-1] and (R,S)-syn- and (S,S)-anti-23 [in
45% yield in a 53:47 ratio derived from (S)-2] (Scheme 6). The oxaz-
olidin-2-one (R)-1 was found to be stereochemically more domi-
nant than its quasi-enantiomeric partner (S)-2 leading to the
corresponding oxazolidin-2-ones (S,R)-syn-10 [with moderate lev-
els of diastereocontrol (66% de)] and (R,S)-syn-23 [with poor levels
of diastereocontrol (6% de)] (Scheme 6). Whereas for the matched
combination of oxazolidin-2-ones (S)-1 and (S)-21, these resolved
efficiently the active ester (rac)-13, to give the corresponding oxaz-
olidin-2-one adducts (R,S)-syn-10 (in 64% yield with 70% d.e.) and
(S,S)-syn-25 (in 59% yield with 70% de) (Scheme 7). Evidently, each
component of this combination of oxazolidin-2-ones resolved each
enantiomer of the active ester (rac)-13 in a near equal and opposite
fashion.
corresponding oxazolidin-2-one adducts (R,S)-syn-10 (in 58% yield
with 86% de) and (S,R)-syn-28 (in 66% yield with 82% de) [for (rac)-
1], and (R,R)-syn-25 (in 53% yield with >90% de) and (R,S)-syn-29
(in 56% yield with 74% de) [for (rac)-21] (Scheme 9).12 The levels
of stereocontrol were found to be excellent and in line with those
obtained for their corresponding mutual kinetic resolutions. These
adducts were separated efficiently by column chromatography
leading to the required diastereoisomerically pure syn-adducts in
good yield {DRF [light petroleum ether (bp 40–60 °C)/diethyl ether]
ꢁ0.1 [for (rac)-1] and 0.18 [for (rac)-21]}.
These types of resolutions can be performed using a combina-
tion of quasi-enantiomeric isotopomeric substrates, such as oxaz-
olidin-2-ones (R)-1 and (S)-[D2]-1, and active esters (R)-13 and
(S)-[D3]-13 (Schemes 10 and 11). For example, deprotonation of
an equimolar combination of oxazolidin-2-ones (R)-1 and (S)-
[D2]-1 using n-BuLi in THF at ꢀ78 °C, followed by the addition of
active ester (rac)-13, gave a separable mixture of diastereoisomeric
oxazolidin-2-ones (S,R)-syn-10/(R,S)-syn-[D2]-10 (with an isotopo-
meric ratio of 52:48 2%) and (R,R)-anti-10/(S,S)-anti-[D2]-10
(with an isotopomeric ratio of 53:47 2%) in 32% and 8% combined
yields, respectively [(S,R)-syn-10/(R,S)-syn-[D2]-10: (R,R)-anti-10/
(S,S)-anti-[D2]-10 = 88:12] (Scheme 10).
With this information in hand, we next turned our attention to
probing the complementary parallel kinetic resolution of oxazoli-
din-2-ones (rac)-1 and (rac)-21 using a combination of quasi-enan-
tiomeric active esters (R)-13 and (S)-27 (Schemes 8 and 9).
Deprotonation of oxazolidin-2-ones (rac)-1 and (rac)-21 with n-
BuLi in THF at ꢀ78 °C, followed by the addition of an equimolar
combination of active esters (R)-13 and (S)-27, gave after 2 h, the
The complementary resolution of oxazolidin-2-one (rac)-1
using a quasi-enantiomeric combination of isotopomers, (R)-13
and (S)-[D3]-13, gave similarly a separable mixture of diastereoiso-
O
HN
O
O
O
O
O
O
Ph
1.
2.
n-BuLi
THF, -78 ºC
(
R
)-1
Ph
Ph
N
O
N
O
OAc
O
OAc
OAc
O
i-Pr
Ph
Ph
HN
O
(
S
,
R
)-syn-10: (
83:17 (48%)
R,R)-anti-10
(R
,
S
)-syn-23: (
S,S)-anti-23
Cl
(
rac)-13
53:47 (45%)
i
-Pr
(S)-2
Scheme 6. Parallel kinetic resolution of active ester (rac)-13 using a mismatched combination of oxazolidin-2-ones (R)-1 and (S)-2.
O
HN
O
O
O
O
O
O
Ph
1. n-BuLi
THF, -78 ºC
Ph
(S)-1
Ph
N
O
N
O
2.
OAc
OAc
EtO2C
O
OAc
Ph
O
Ph
HN
O
(R,S)-syn-10: (S,S)-anti-10
(S,S)-syn-25: (R,S)-anti-25
Cl
85:15 (59%)
(rac)-13
85:15 (64%)
EtO2C
(S)-21
Scheme 7. Parallel kinetic resolution of active ester (rac)-13 using a matched combination of oxazolidin-2-ones (S)-1 and (S)-21.

S. Chavda et al. / Tetrahedron Letters 49 (2008) 7398–7402
7401
MeO
O
O
O
O
O
1. n-BuLi
THF, -78 ºC
Ph
N
O
HN
O
N
O
2. (R)-13
(S)-27
Me
H
H
OAc
Ph
Ph
Ph
(rac)-1
(R,S)-syn-10: (S,S)-anti-10
(S,R)-syn-28: (R,R)-anti-28
91:9 (66%)
93:7 (58%)
MeO
O
O
O
O
O
1. n-BuLi
THF, -78 ºC
Ph
N
O
N
O
HN
O
2. (R)-13
(S)-27
Me
H
H
OAc
EtO2C
EtO2C
EtO2C
(rac)-21
(R,R)-syn-25: (S,R)-anti-25
(R,S)-syn-29: (S,S)-anti-29
>95:<5 (53%)
87:13 (56%)
Scheme 9. Parallel kinetic resolution of oxazolidin-2-ones (rac)-1 and (rac)-21 using quasi-enantiomeric active esters (R)-13 and (S)-27.
(S,R)-syn-10:(R,R)-anti-10; 88:12
O
O
O
O
O
Ph
Ph
HN
Ph
O
N
O
N
O
AcO
H
H
OAc
Ph
(S,R)-syn-10
Ph
(R,R)-anti-10
(R)-1
1. n-BuLi
THF, -78 ºC
53:47 ( 2%); 8%
52:48 ( 2%); 32%
OAc
2.
O
O
O
O
O
O
Ph
Ph
Ph
AcO
O
HN
O
N
O
N
O
Cl
(rac)-13
H
OAc
Ph
H
D
D
D
Ph
(S)-[D2]-1
Ph
D
D
D
(S,S)-anti-[D2]-10
(R,S)-syn-[D2]-10:(S,S)-anti-[D2]-10; 88:12
(R,S)-syn-[D2]-10
Scheme 10. Parallel kinetic resolution of active ester (rac)-13 using a quasi-enantiomeric mixture of isotopomeric oxazolidin-2-ones (R)-1 and (S)-[D2]-1.
(R,S)-syn-10: (S,R)-anti-10; 85:15
O
O
O
O
Ph
Ph
N
O
N
O
H
OAc
H
OAc
Ph
(R,S)-syn-10
Ph
(R,R)-anti-10
O
1. n-BuLi
THF, -78 ºC
50:50 ( 2%); 34%
HN
Ph
O
50:50 ( 2%); 7%
Cl
Cl
2.
O
O
O
O
O
Ph
Ph
Ph
O
(rac)-1
N
O
N
O
H
OAc
O
(R)-13
D3COCO
H
D3COCO
H
Ph
(S,R)-syn-[D3]-10
(S,R)-syn-[D3]-10: (S,S)-anti-[D3]-10; 85:15
Scheme 11. Parallel kinetic resolution of oxazolidin-2-one (rac)-1 using a quasi-enantiomeric mixture of isotopomeric active esters (R)-13 and (S)-[D3]-13.
Ph
Ph
D3COCO
O
(S,S)-anti-[D3]-10
H
(S)-[D3]-13
meric oxazolidin-2-ones (R,S)-syn-10/(S,R)-syn-[D3]-10 (with an
isotopomeric ratio of 50:50 2%) and (R,R)-anti-10/(S,S)-anti-[D3]-
10 (with an isotopomeric ratio of 50:50 2%) in 34% and 7% com-
bined yields, respectively [(R,S)-syn-10/(S,R)-syn-[D3]-10: (R,R)-
anti-10/(S,S)-anti-[D3]-10 = 85:15] (Scheme 11). These particular
parallel kinetic resolutions behave similarly to their non-labelled
mutual kinetic resolution involving the non-labelled parent oxaz-
olidin-2-one (rac)-1 and active ester (rac)-13 (as shown in Scheme
4, entry 3). Interestingly, the use of quasi-enantiomeric isotopo-
mers, such as (R)-13/(S)-[D3]-13, as distinguishable enantiomers13

7402
S. Chavda et al. / Tetrahedron Letters 49 (2008) 7398–7402
O
cial selectivity were also found to be dependent on the structural
O
O
nature of the oxazolidin-2-one.
Ph
LiOH, H2O2
Ph
Ph
OH
N
O
O
THF, H2O (3:1)
H
OAc
Acknowledgements
OAc
Ph
(R)-8; 55%
We are grateful to Syngenta for funding (to S.C.), to the EPSRC
for a studentship (to E.C.) and to the EPSRC National Mass Spec-
trometry Service (Swansea) for accurate mass determinations.
(R,R)-anti-10
O
O
O
Ph
AcO
LiOH, H2O2
OH
N
THF, H2O (3:1)
References and notes
H
OAc
Ph
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4. (a) Ohta, T.; Takaya, H.; Kitamura, M.; Nagai, K.; Noyori, R. J. Org. Chem. 1987,
52, 3174–3176; (b) Stille, J. K.; Parrinello, G. J. Mol. Catal. 1983, 21, 203–210; (c)
Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J. Chem. Soc., Chem. Commun.
1991, 485–486; (d) Franck, A.; Ruchardt, C. Chem. Lett. 1984, 1431–1434.
5. For reviews on parallel kinetic resolution see: (a) Eames, J. Angew. Chem., Int. Ed.
2000, 39, 885–888; (b) Eames, J. In Organic Synthesis Highlights; VCH-Wiley,
2003; Vol. v, Chapter 17; (c) Dehli, J. R.; Gotor, V. Chem. Soc. Rev. 2002, 31, 365–
370; (d) Dehli, J. R.; Gotor, V. ARKIVOC 2002, v, 196–202.
6. For recent examples see: (a) Liao, L.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J.
M. J. Am. Chem. Soc. 2004, 126, 4490–4491; (b) Davies, S. G.; Garner, A. C.; Long,
M. J.; Morrison, R. M.; Roberts, P. M.; Savory, E. D.; Smith, A. D.; Sweet, M. J.;
Withey, J. M. Org. Biomol. Chem. 2005, 3, 2762–2775; (c) Vedejs, E.; Chen, X. J.
Am. Chem. Soc. 1997, 119, 2584–2585; (d) Daugulis, O.; Vedejs, E. J. Am. Chem.
Soc. 2003, 125, 4166–4173.
7. (a) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Motevalli, M.; Northen,
J.; Yohannes, Y. Synlett 2006, 101–105; (b) Boyd, E.; Coulbeck, E.; Coumbarides,
G. S.; Chavda, S.; Dingjan, M.; Eames, J.; Flinn, A.; Motevalli, M.; Northen, J.;
Yohannes, Y. Tetrahedron: Asymmetry 2007, 18, 2515–2530; (c) Coumbarides, G.
S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron Lett.
2005, 46, 2897–2902.
8. (a) Coumbarides, G. S.; Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron
Lett. 2005, 46, 849–853; (b) Chavda, S.; Coulbeck, E.; Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Ghilagaber, S.; Yohannes, Y. Tetrahedron: Asymmetry
2006, 17, 3386–3399.
9. For a comprehensive review into quasi-enantiomers see: Zhang, Q.; Curran, D.
P. Chem. Eur. J. 2005, 11, 4866–4880.
10. Boyd, E.; Chavda, S.; Eames, J.; Yohannes, Y. Tetrahedron: Asymmetry 2007, 18,
476–482.
11. 2-Acetyl mandelic acid (rac)-8 was formed in 80% yield by treatment of
mandelic acid (rac)-7 with acetyl chloride.
(S)-8; 86%
(S,R)-syn-10
Scheme 12. Hydrolysis of oxazolidin-2-ones (R,R)-anti-10 and (S,R)-syn-10.
allows the stereocontrol to be monitored efficiently by either 1H
NMR spectroscopy14 or mass spectrometry.15
Access to both enantiomers of acetyl mandelic acid (R)- and (S)-
8 was achieved in good yields through simple hydrolysis [LiOH/
H2O2 (1 equiv) in THF/H2O (3:1)] of the corresponding oxazo-
lidin-2-one adducts (R,R)-anti- and (S,R)-syn-10, respectively
(Scheme 12). The absolute stereochemistry was assigned by com-
parison with the literature optical rotation values.16 The optical
purity was determined using a chiral shift NMR reagent, tris[3-(tri-
fluoromethylhydroxy-methylene)-d-camphorato] europium(III).17
The nearest analogy to this work is that reported by Davies and
co-workers.18 They reported the kinetic resolution of 2-acetoxy-2-
phenylacetyl chloride using 4-substituted and 4,5,5-trisubstituted
oxazolidin-2-ones, such as (S)-2, to give predictably, the comple-
mentary oxazolidin-2-one adducts, such as anti-23, with moderate
to excellent levels of diastereocontrol (ꢁ30–66% de). We have re-
ported for 4-phenyloxazolidin-2-one (rac)-1 a subtle change in
the enantiomeric recognition process for active esters, such as
(rac)-13, favouring formation of the syn-adduct 10 (in 76% de),
whereas the related acid chloride19 favoured formation of the
anti-adduct 10 (in 66% de).
High levels of mutual recognition and diastereocontrol were
achieved with (lithiated) oxazolidin-2-one 1 by removing the po-
tential for competitive co-ordination and steric congestion at both
the C(2) and C(6)-positions of the phenolate pro-leaving groups
within the 2-acetyl mandelates (rac)-12–14. Active esters, such
as (rac)-9 and (rac)-16, which contain a halo-substituent at either
the C(2) or the C(6)-positions, gave little or no levels of diastereo-
control. For good chemical yield, the pro-leaving group must have a
moderately electron-withdrawing nature.
We had previously shown that high levels of syn-diastereoselec-
tion can be obtained using a related active ester, pentafluorophenyl
2-methoxy-2-phenyl-acetate (rac)-6. Replacing the 2-MeO substi-
tuent10 [in (rac)-6] for a less co-ordinating 2-AcO substituent [in
(rac)-9] lowered the overall level of diastereocontrol. Removing
competitive co-ordination and steric congestion within the pro-
leaving group19,20 [as in (rac)-12] and thus promoting the co-ordi-
nating nature of the 2-AcO substituent gave high levels of syn-dia-
stereoselectivity (74% de).
In conclusion, we have reported the parallel kinetic resolution
of racemic 2-acetoxy-2-phenyl acetic acid using an equimolar
combination of quasi-enantiomeric oxazolidin-2-ones. For efficient
resolution, this methodology was found to be dependent on the
structural nature of the active ester and its pro-leaving group. High
levels of mutual recognition were achieved using the 4-chloro-
phenyl active ester (rac)-13 and an equimolar combination of qua-
si-enantiomeric oxazolidin-2-ones [e.g., (S)-1 and (S)-21] leading to
separable diastereoisomerically pure oxazolidin-2-one adducts 10
and 25 in good yields. The levels of diastereoselectivity and the fa-
12. Active esters derived from pentafluorophenol are more electrophilic than those
derived from 4-chlorophenol. For example, pentafluorophenyl 2-phenylacetyl
mandelate was found to be around eleven times more reactive than 4-
chlorophenyl 2-acetyl mandelate towards (lithiated) 4-phenyl-oxazolidin-2-
one 1.
13. Eames, J.; Suggate, M. J. J. Label. Compd. Radiopharm. 2004, 47, 705–717.
14. For a related study, see: (a) Chavda, S.; Coumbarides, G. S.; Dingjan, M.; Eames,
J.; Flinn, A.; Northen, J. Chirality 2007, 19, 313–320; (b) Coumbarides, G. S.;
Dingjan, M.; Eames, J.; Flinn, A.; Northen, J. Chirality 2007, 19, 321–328.
15. (a) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166–4173; (b) Boyd, E.;
Chavda, S.; Coulbeck, E.; Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.;
Krishnamurthy, A. K.; Namutebi, M.; Northen, J.; Yohannes, Y. Tetrahedron:
Asymmetry 2006, 17, 3406–3422; (c) Taji, H.; Watanabe, M.; Harara, N.; Naoki,
H.; Ueda, Y. Org. Lett. 2002, 4, 2699–2702; (d) Reetz, M. T.; Becker, M. H.; Klein,
H. W.; Stockigt, D. Angew. Chem., Int. Ed. 1999, 38, 1758–1761.
16. For example, (S)-8; ½a D25
ꢂ
+132.2 (c 4.1, CHCl3); lit. ½a D25
ꢂ
+107.8 (c 1.25, CHCl3)—
see: Ebbers, E. J.; Ariaans, G. J. A.; Bruggink, A.; Zwanenburg, B. Tetrahedron:
Asymmetry 1999, 10, 3701–3718; lit. ½a D20
ꢂ
+151 (c 2.55, acetone)—see: Philippe,
N.; Denivet, F.; Vasse, J.-L.; Santos, J. S. O.; Levacher, V.; Dupas, G. Tetrahedron
2003, 59, 8049–8056.
17. Determined by the splitting (ꢁ6.9 Hz) of the methyl singlet at 2.10 ppm
(measured at 400 MHz using 1H NMR spectroscopy).
18. Bew, S. P.; Davies, S. G.; Fukuzawa, S.-I. Chirality 2000, 12, 483–487.
19. Chavda, S. PhD Thesis, University of London, 2008.
20. Mutual kinetic resolution of pentafluorophenyl and 4-chlorophenyl 2-
methoxy-2-phenyl-acetates
using
4-phenyl-oxazolidin-2-one
(rac)-1
favoured formation of the corresponding syn-adducts with 72% de and 76%
de, respectively.